PROJECT SUMMARY/ABSTRACT A major issue in cancer therapy and management is the development of drug resistance, which occurs through a variety of distinct mechanisms including both cancer cell autonomous and non-cell autonomous mechanisms. Despite recent progress in understanding cell autonomous mechanisms of resistance in prostate cancer, such as target amplification/mutation, signaling bypass and cellular lineage plasticity, drug resistance in a large number of patients remains unexplained. This proposal aims to investigate the role of tumor microenvironment (TME) in mediating non-cell autonomous mechanisms of tumor progression and resistance to targeted cancer therapy. The long-term objective is to identify druggable components in the TME and to effectively target those components to treat cancer. My doctoral research focuses on a specific stromal component of TME, the cancer associated fibroblasts (CAFs), and how they contribute to antiandrogen resistance in prostate cancer (PCa). Using a recently developed PCa model called 22Pc-EP, which can progress from hormone nave to hormone resistant stage and contains its own CAFs (22Pc-CAFs), I have demonstrated that these CAFs are able to promote the tumor growth and resistance to antiandrogens observed in this line through the action of unidentified secreted protein factors. Despite the fact that 22Pc-EP growth and survival is normally androgen dependent, the CAFs in 22Pc-CAF can promote growth even while androgen receptor (AR) signaling is suppressed, indicating that growth and survival effect works through a different mechanism and bypassing AR activation. To elucidate the precise mechanism of this resistance, two important points must be addressed: what is the signaling event driving growth and survival in 22Pc-EPs? (Aim 1) And what is the CAF secreted factor that triggers such growth and survival in 22Pc-EPs? (Aim 2) The findings from my doctoral work will provide a mechanistic insight into how secreted factors from CAFs help to promote resistance to AR targeted therapies. This work will have implications for treating metastatic disease as the microenvironment of PCa bone metastases are known to contain fibroblasts. For my postdoctoral research, I plan to build on this work to study how stromal components within the tumor microenvironment mediate tumor progression and therapy resistance by developing a new mouse model based on human cancer genomics. (Aim 3) Taken together, my current work and future plans will enhance our understanding about the dynamic signaling and communication between cancer cells and their surrounding microenvironment, will also illuminate potential therapeutic targets in the setting of drug resistant, metastatic prostate cancer.